Pancreatic cancer represents the fifth leading cause of cancer death in the United States and has the worst prognosis of all gastrointestinal cancers with 5 year survival rates less than 5 percent. It is of paramount importance to develop model systems with early lesions of pancreatic cancers to facilitate the diagnosis and therapy for this deadly disease. The purpose of this application is to study the role of TGF-beta in pancreatic cancer pathogenesis using a transgenic mouse model that we recently generated. TGF-beta has been postulated to play an important role in the development of pancreatic cancers as more than 50 percent of human pancreatic cancers bear mutations of Smad4, a critical protein required for TGF-beta signaling. We generated a transgenic mouse model with pancreas-specific overexpression of Smad7, a specific inhibitor of TGF-beta signaling. At 6 months of age, most transgenic animals developed premalignant ductal lesions in the pancreas with characteristics of pancreatic intraepithelial neoplasia (PanIN), a precursor to invasive pancreatic cancers. We will utilize this unique mouse model to analyze the functional interaction between TGF-beta and environmental factors and other genetic changes in the tumorigenesis of pancreatic cancers. (1) We will determine if disruption of TGF-beta signaling is able to accelerate chemical carcinogen-induced pancreatic cancer formation. Specifically, we will analyze the susceptibility of the mice with pancreas- specific Smad7 expression to the malignant lesions induced by an alkylating agent NMU (N-Nitroso-N-Methyl Urea). (2) We will determine the functional interaction between TGF-beta and p53 in pancreatic cancer formation. We will study the hypothesis that TGF-beta disruption by Smad7 overexpression is able to cooperate with loss of p53 to accelerate pancreatic cancer formation. Taken together, these studies will not only help to understand the molecular pathogenesis of pancreatic cancers, but also aid in future designs of strategies for early detection and early therapy to combat this deadly disease. Lay language description: This proposal is to use animal models to study the function of TGF-beta pathway in carcinogenesis of pancreatic cancers. [unreadable] [unreadable] REVISED: February 27, 2006 (See Revision Note) [unreadable] [unreadable] [unreadable]